Neutrophils differentially attenuate immune response to Aspergillus infection through complement receptor 3 and induction of myeloperoxidase.

Invasive aspergillosis (IA) remains a major cause of morbidity in immunocompromised hosts. This is due to the inability of the host immunity to respond appropriately to Aspergillus. An established risk factor for IA is neutropenia that is encountered by patients undergoing chemotherapy. Herein, we investigate the role of neutrophils in modulating host response to Aspergillus. We found that neutrophils had the propensity to suppress proinflammatory cytokine production but through different mechanisms for specific cytokines. Cellular contact was requisite for the modulation of interleukin-1 beta production by Aspergillus with the involvement of complement receptor 3. On the other hand, inhibition of tumour necrosis factor-alpha production (TNF-α) was cell contact-independent and mediated by secreted myeloperoxidase. Specifically, the inhibition of TNF-α by myeloperoxidase was through the TLR4 pathway and involved interference with the mRNA transcription of TNF receptor-associated factor 6/interferon regulatory factor 5. Our study illustrates the extended immune modulatory role of neutrophils beyond its primary phagocytic function. The absence of neutrophils and loss of its inhibitory effect on cytokine production explains the hypercytokinemia seen in neutropenic patients when infected with Aspergillus.

Tissue penetration of antifungal agents.

Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection.

An elevated pro-inflammatory cytokine response is linked to development of amphotericin B-induced nephrotoxicity.

OBJECTIVES: The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD). PATIENTS AND METHODS: In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis. RESULTS: The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI. CONCLUSIONS: In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury.

Early serum galactomannan trend as a predictor of outcome of invasive aspergillosis.

The monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of ≥ 0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 ± 0.12 and 1.15 ± 0.22, respectively; P = 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of <0.5 (n = 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% (P = 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.

Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients.

Voriconazole is approved for treating invasive fungal infections. We examined voriconazole exposure-response relationships for patients from nine published clinical trials. The relationship between the mean voriconazole plasma concentration (C(avg)) and clinical response and between the free C(avg)/MIC ratio versus the clinical response were explored using logistic regression. The impact of covariates on response was also assessed. Monte Carlo simulation was used to estimate the relationship between the trough concentration/MIC ratio and the probability of response. The covariates individually related to response were as follows: study (P < 0.001), therapy (primary/salvage, P < 0.001), primary diagnosis (P < 0.001), race (P = 0.004), baseline bilirubin (P < 0.001), baseline alkaline phosphatase (P = 0.014), and pathogen (yeast/mold, P < 0.001). The C(avg) for 72% of the patients was 0.5 to 5.0 µg/ml, with the maximum response rate (74%) at 3.0 to 4.0 µg/ml. The C(avg) showed a nonlinear relationship to response (P < 0.003), with a lower probability at the extremes. For patients with C(avg) < 0.5 µg/ml, the response rate was 57%. The lowest response rate (56%) was seen with a C(avg) ≥ 5.0 µg/ml (18% of patients) and was associated with significantly lower mold infection responses compared to yeasts (P < 0.001) but not with voriconazole toxicity. Higher free C(avg)/MIC ratios were associated with a progressively higher probability of response. Monte Carlo simulation suggested that a trough/MIC ratio of 2 to 5 is associated with a near-maximal probability of response. The probability of response is lower at the extremes of C(avg). Patients with higher free C(avg)/MIC ratios have a higher probability of clinical response. A trough/MIC ratio of 2 to 5 can be used as a target for therapeutic drug monitoring.

Early proinflammatory cytokines and C­reactive protein trends as predictors of outcome in invasive Aspergillosis.

BACKGROUND: Monitoring treatment response in invasive aspergillosis is challenging, because an immunocompromised host may not exhibit reliable symptoms and clinical signs. Cytokines play a pivotal role in mediating host immune response to infection; therefore, the profiling of biomarkers may be an appropriate surrogate for disease status. METHODS: We studied, in a cohort of 119 patients with invasive aspergillosis who were recruited in a multicenter clinical trial, serum interleukin (IL)-6, IL­8, IL­10, interferon­Î³, and C­reactive protein (CRP) trends over the first 4 weeks of therapy and correlated these trends to clinical outcome parameters. RESULTS: Circulating IL­6 and CRP levels were high at initiation of therapy and generally showed a downward trend with antifungal treatment. However, subjects with adverse outcomes exhibited a distinct lack of decline in IL­6 and CRP levels at week 1, compared with responders (P = .02, for both IL­6 and CRP). Nonresponders also had significantly elevated IL­8 levels (P = .001). CONCLUSIONS: High initial IL­8 and persistently elevated IL­6, IL­8, and CRP levels after initiation of treatment may be early predictors of adverse outcome in invasive aspergillosis. Cytokine and CRP profiles could be used for early identification of patients with a poor response to antifungal treatment who may benefit from more­aggressive antimicrobial regimens.

International retrospective analysis of 73 cases of invasive fusariosis treated with voriconazole.

The outcomes for 73 invasive fusariosis patients treated with voriconazole were investigated. Patients with proven (n = 67) or probable (n = 6) infections were identified from the voriconazole clinical database (n = 39) and the French National Reference Center for Mycoses and Antifungals database (n = 34). Investigator-determined success was a complete or partial response. Survival was determined from day 1 of voriconazole therapy to the last day known alive. Patients were 2 to 79 years old (median, 43 years), and 66% were male. Identified Fusarium species (62%) were F. solani, F. moniliforme, F. proliferatum, and F. oxysporum. Underlying conditions analyzed included hematopoietic stem cell transplant (HSCT; 18%), hematologic malignancy (HM; 60%), chronic immunosuppression (CI; 12%), or other condition (OC; 10%). Infection sites were brain (5%), disseminated excluding brain (67%), lungs/sinus (15%), and other (12%). Most patients (64%) were or had recently been neutropenic (<500 cells/mm(3)). Therapy duration was 1 to 480 days (median, 57 days), with a 47% success rate. Baseline neutropenia impacted success adversely (P ≤ 0.03). Success varied by underlying condition (HSCT, 38%; HM, 45%; CI, 44%; OC, 71%) and infection site (brain, 0%; disseminated, 45%; other, 56%; lung/sinus, 64%) (P > 0.05). Combination therapy (13 patients) was no better than treatment with voriconazole alone. Overall, 59% of the patients died (49% died of fusariosis), and 90-day survival was 42%. Site of infection influenced survival (P = 0.02). Median survival (in days) by species was as follows: F. solani, 213; F. oxysporum, 112; Fusarium spp., 101; F. proliferatum, 84; F. moniliforme, 76. We conclude that voriconazole is a therapeutic option for invasive fusariosis.

Pharmacokinetics and safety of 14 days intravenous voriconazole in allogeneic haematopoietic stem cell transplant recipients.

BACKGROUND: Voriconazole is used to manage invasive fungal diseases in recipients of an allogeneic haematopoietic stem cell transplant (HSCT) after myeloablative treatment. Little is known about the pharmacokinetics (PK) of voriconazole in this population, who also receive cyclosporine A. METHODS: Patients admitted for an allogeneic HSCT were eligible for the study. Voriconazole was given intravenously at 6 mg/kg twice daily on day 1, then 4 mg/kg twice daily until the day of transplant to reach steady-state conditions and then continued for a further week during which cyclosporine A was administered. Blood samples were drawn on the day of HSCT and daily for the next 14 days. PK curves were determined on days 7 and 14. PK parameters were calculated using non-compartmental analysis. CYP2C19*2 and CYP2C19*3 polymorphisms were also determined. RESULTS: Ten patients were fully evaluable. Median AUC(0-12) of voriconazole on the day of HSCT was 33.81 mg.h/L [interquartile range (IQR) 20.59-39.39] and 25.61 mg.h/L (IQR 22.48-38.65) 1 week later. AUC(0-12) of voriconazole on both days was similar to data reported for healthy volunteers. Trough levels were <1.0 mg/L for 3 of 10 patients on the day of HSCT and for 4 of 10 patients 1 week later. No difference in clearance of voriconazole was found between CYP2C19 extensive metabolizers (n = 4) and carriers of one non-functional allele (n = 6). CONCLUSIONS: Exposure and clearance of voriconazole in recipients of an allogeneic HSCT are similar to those of healthy volunteers though there was high intra- and inter-individual variation in drug exposures which may have implications for similar patient populations.

Association of mannose-binding lectin deficiency with acute invasive aspergillosis in immunocompromised patients.

BACKGROUND: Invasive aspergillosis is a devastating infection with attributable mortality of 40% despite antifungal therapy. In animal models of aspergillosis, deficiency of mannose-binding lectin (MBL), a pattern recognition receptor that activates complement, is a susceptibility factor. MBL deficiency occurs in 20%-30% of the population. We hypothesized that MBL deficiency may be a susceptibility factor for invasive aspergillosis in humans. METHODS: Serum MBL concentrations were measured by enzyme-linked immunosorbent assay in 65 patients with proven or probable acute invasive aspergillosis and 78 febrile immunocompromised control subjects. MBL concentrations and the frequency of MBL deficiency were compared. RESULTS: The median serum MBL level was significantly lower in patients with aspergillosis than in control subjects (281 ng/mL vs 835 ng/mL; P = .007). MBL deficiency (MBL concentration, <500 ng/mL) was significantly more common in patients with aspergillosis than control subjects (62% vs 32%; P < .001). Frequency of MBL deficiency was similar among patients with aspergillosis irrespective of response to antifungal therapy (P = .10). CONCLUSIONS: This study is the first, to our knowledge, to show an association between MBL deficiency and acute invasive aspergillosis in humans. Further study is required to investigate the causal nature of this association and to define whether diagnosis of MBL deficiency may identify immunocompromised patients at increased risk of invasive aspergillosis.

Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients.

The efficacy of voriconazole in 107 patients with scedosporiosis was analyzed. Principal infection sites were the lungs/sinuses (24%), central nervous system (CNS) (20%), and bone (18%), while 21% of patients had disseminated infection. Solid organ transplantation (22%), hematological malignancy (21%), and surgery/trauma (15%) were the predominant underlying conditions. A successful therapeutic response was achieved in 57% of patients (median, 103 therapy days), with > 98% of those responding receiving > or = 28 days of therapy. Patients receiving primary therapy showed a 61% response versus 56% for the others. The best therapeutic responses were seen for skin/subcutaneous (91%) or bone (79%) infections, and the lowest for CNS infections (43%). Patients without major immune suppression (72%) or those with solid organ transplantation (63%) or various hematological conditions (60%) showed the best responses by underlying condition. Median known survival time was 133 days (therapy successes, 252 days; failures, 21 days). In all, 43 (40%) patients died, 73% due to scedosporiosis. Patients with Scedosporium prolificans infection had significantly reduced survival times (P = 0.0259) and were more likely to die from fungal infection (P = 0.002) than were Scedosporium apiospermum-infected patients. In a subset of 43 patients where voriconazole baseline MICs were available, response to voriconazole was higher for S. apiospermum-infected patients (54% response; MIC(50), 0.25 microg/ml) than for S. prolificans-infected patients (40% response; MIC(50), 4.0 microg/ml). Voriconazole demonstrated clinically useful activity in the treatment of both S. apiospermum and S. prolificans infections and was well tolerated.

Activities of voriconazole, itraconazole and amphotericin B in vitro against 590 moulds from 323 patients in the voriconazole Phase III clinical studies.

INTRODUCTION: Fungal pathogens from the voriconazole trials were identified and tested for susceptibility at two reference laboratories. METHODS: MICs were measured using CLSI M38-A 48 h microdilution methodology. RESULTS: Moulds from 29 genera and 38 species were isolated from 18 countries. Aspergillus spp. predominated (69%), followed by Scedosporium spp. (11.5%). Aspergillus fumigatus (292/590, 49.5%) was the most common species, followed by Scediosporium apiospermum (9.7%) and Aspergillus terreus (7.3%). The bronchi, lungs and sinuses yielded 45% of the isolates (57% of aspergilli), with 24% from the oropharynx/oesophagus. Other sites included blood/catheter (7.3%) and CNS (5.2%). MIC90s of itraconazole and voriconazole for Aspergillus spp. were the same (0.5 mg/L), but 17 Aspergillus isolates were itraconazole-resistant (MICs > or = 1-16 mg/L). Additionally, in 31 A. fumigatus and 23 A. terreus isolates, amphotericin MICs were > or = 2.0 mg/L. Voriconazole MICs exceeded 4 mg/L in only 5.8% (34/590) of the isolates, including one A. fumigatus (8.0 mg/L), 9/11 Scedosporium prolificans, 10/13 Fusarium solani and all 9 Zygomycetes. Most were also not susceptible to itraconazole or amphotericin B. A notable increase in MIC (more than two doubling dilutions) during voriconazole therapy was seen for one A. fumigatus isolate. The response rate of voriconazole-treated patients with isolate MICs > or = 4.0 mg/L was 38% when compared with 52% for those with MICs < 4.0 mg/L. CONCLUSIONS: Voriconazole shows activity, in vitro, similar to that of itraconazole against a wide range of moulds. It is also active against some isolates not susceptible to itraconazole or amphotericin B, but not the Zygomycetes. The relationship between voriconazole MIC and clinical outcome requires further study.

Activity of voriconazole, itraconazole, fluconazole and amphotericin B in vitro against 1763 yeasts from 472 patients in the voriconazole phase III clinical studies.

The susceptibility of 1763 yeast isolates (from 22 species and seven genera) was tested using Clinical and Laboratory Standards Institute M27-A2 microdilution methodology. Candida spp. predominated (97.1%), mainly C. albicans (51.4%), C. glabrata (16.4%) and C. tropicalis (13.7%), followed by Trichosporon spp. (1.1%) and Cryptococcus neoformans (1.0%). Most isolates came from blood/catheters (72.0%) or the oesophagus/oropharynx (11.3%). The voriconazole, itraconazole, fluconazole and amphotericin B MIC90 values (minimum inhibitory concentration for 90% of the isolates) for all isolates were 1.0, 2.0, 64 and 1.0 microg/mL, respectively. Voriconazole MICs correlated with those for fluconazole (r = 0.91) and itraconazole (r = 0.90). Only 109 isolates (6.2%) had voriconazole MICs > or = 4.0 microg/mL; all were C. albicans, C. glabrata or C. tropicalis resistant to itraconazole (and most to fluconazole). Isolates from 22 patients with amphotericin MICs > or = 2.0 microg/mL (range 2.0-16.0 microg/mL) were also cross-resistant to one or more of the triazoles. Patients (n = 34) with voriconazole-resistant isolates showed a 56% response to voriconazole therapy, and those patients (n = 261) with susceptible isolates showed a 71% response. Twenty-three voriconazole-treated patients had baseline resistant isolates, in eight patients voriconazole resistance developed during therapy and in three patients a different resistant species arose during therapy. Thus, voriconazole MICs correlate with those of fluconazole and itraconazole and may predict clinical outcome.

Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign.

BACKGROUND: Computed tomography (CT) of the chest may be used to identify the halo sign, a macronodule surrounded by a perimeter of ground-glass opacity, which is an early sign of invasive pulmonary aspergillosis (IPA). This study analyzed chest CT findings at presentation from a large series of patients with IPA, to assess the prevalence of these imaging findings and to evaluate the clinical utility of the halo sign for early identification of this potentially life-threatening infection. METHODS: Baseline chest CT imaging findings from 235 patients with IPA who participated in a previously published study were systematically analyzed. To evaluate the clinical utility of the halo sign for the early identification and treatment of IPA, we compared response to treatment and survival after 12 weeks of treatment in 143 patients who presented with a halo sign and in 79 patients with other imaging findings. RESULTS: At presentation, most patients (94%) had > or =1 macronodules, and many (61%) also had halo signs. Other imaging findings at presentation, including consolidations (30%), infarct-shaped nodules (27%), cavitary lesions (20%), and air-crescent signs (10%), were less common. Patients presenting with a halo sign had significantly better responses to treatment (52% vs. 29%; P<.001) and greater survival to 84 days (71% vs. 53%; P<.01) than did patients who presented with other imaging findings. CONCLUSIONS: Most patients presented with a halo sign and/or a macronodule in this large imaging study of IPA. Initiation of antifungal treatment on the basis of the identification of a halo sign by chest CT is associated with a significantly better response to treatment and improved survival.

Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.

BACKGROUND: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. METHODS: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. RESULTS: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients). CONCLUSIONS: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B.

Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities.

This study investigated the relationship between plasma voriconazole concentrations (pVC) and risk of visual adverse events (VAEs) or liver function test (LFT) abnormalities using longitudinal logistic regression. Seven-day mean pVC were calculated from 2,925 plasma samples (1,053 patients); in each 7-day period, the presence or absence of VAEs/abnormal LFTs was analyzed as a binary outcome variable. There was a relationship between pVC and risk of VAE (P = .011) and a weaker, but statistically significant, association with risk of aspartate transaminase (AST), alkaline phosphatase (ALP), or bilirubin but not alanine transaminase (ALT) abnormalities. The odds ratios of LFT abnormalities per 1 mug/mL pVC increase ranged from 1.07 to 1.17. Maximum weekly occurrences were 10%, 8%, 5%, and 14% for AST, ALT, ALP, and bilirubin abnormalities, respectively. Receiver-operating characteristic curve analysis indicates that individual pVC cannot be used to predict subsequent LFT abnormalities.

Strategy of following voriconazole versus amphotericin B therapy with other licensed antifungal therapy for primary treatment of invasive aspergillosis: impact of other therapies on outcome.

BACKGROUND: In a previous randomized trial of voriconazole versus amphotericin B deoxycholate for primary therapy of invasive aspergillosis, voriconazole demonstrated superior efficacy and better survival. In that trial, treatment with voriconazole or amphotericin B deoxycholate could be followed with other licensed antifungal therapies (OLAT). Here, we report the impact of OLAT on the outcome of patients with invasive aspergillosis. METHODS: Data on dose, duration, and the reason for switching to the first OLAT were analyzed, and outcome at week 12 was assessed. RESULTS: Fewer patients in the voriconazole group (52 [36%] of 144) switched to OLAT, compared with patients in the amphotericin B deoxycholate group (107 [80%] of 133). Lipid formulations of amphotericin B were the most common OLAT (38% of patients). Switches were made because of intolerance or insufficient response in 70% for patients in the amphotericin B deoxycholate group, compared with 24% of patients in the voriconazole group. Favorable responses to OLAT in the amphotericin B deoxycholate group occurred in only 19% of patients with initial insufficient response and 38% of patients with intolerance. Salvage therapy with a lipid formulation of amphotericin B after initial treatment with amphotericin B deoxycholate was successful for only 30% of patients (14 of 47). Treatment success among patients randomized to receive amphotericin B, including those whose treatment was switched to OLAT, was 32%, compared with 55% among patients who received voriconazole alone (P<.001). CONCLUSIONS: This study highlights the limited efficacy of salvage antifungal therapy, including therapy with lipid formulations of amphotericin B, and demonstrates the importance of effective initial therapy in invasive aspergillosis.

Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients.

We characterized voriconazole concentrations in the cerebrospinal fluid (CSF) of immunocompetent guinea pigs and patients with invasive fungal infections. In animals, after receipt of oral doses of 4 or 10 mg/kg every 8 h, the mean ratios of CSF to plasma total and free drug concentration were 0.68 and 1.3, respectively. In humans, 1-10 h after receipt of voriconazole, the CSF concentrations ranged from 0.08 to 3.93 microg/mL, and the ratio of CSF to plasma concentration ranged from 0.22 to 1.0 (median, 0.46).

Voriconazole or amphotericin B as primary therapy yields distinct early serum galactomannan trends related to outcomes in invasive aspergillosis.

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response.

Poor efficacy of amphotericin B-based therapy in CNS aspergillosis.

Recently, improved response and survival rates in patients treated with voriconazole and neurosurgery for central nervous system (CNS) aspergillosis have been reported. We assessed retrospectively the outcome in 17 patients with definite or probable CNS aspergillosis treated with amphotericin B alone (n = 15) or in combination with 5-fluorocytosine (n = 3) or itraconazole (n = 2). Four patients underwent neurosurgery. The mortality rate was 100% with a median survival of only 10 days (range: 3-60) after onset of first symptoms or first radiological evidence of CNS aspergillosis. In conclusion, treatment with amphotericin B and itraconazole has negligible efficacy in CNS aspergillosis.